Cardiac contraction in a healthy human heart is initiated by spontaneous excitation of the sinoatrial (“SA”) node, which is located in the right atrium. The electric impulse generated by the SA node travels to the atrioventricular (“AV”) node where it is transmitted to the bundle of His and to the Purkinje network. The fibers in the Purkinje network branch out in many directions to facilitate coordinated contraction of the left and right ventricles, thus providing natural pacing. In some disease states, the heart loses some of its natural capacity to pace properly. Such dysfunction is commonly treated by implanting a pacemaking device that generates an electronic pulse.
While effectively improving the lives of many patients, such implantable pacemakers have certain technical limitations. For example, implantable pacemakers rely on a self-contained power source such as a battery and consequently have a limited lifetime before the power source is in need of replacement. Hence, an otherwise healthy patient may require multiple surgeries to replace the power source or the entire implantable pacemaker. In addition, implantable pacemaker batteries are large and are usually the bulkiest pacemaker component. A pacemaker's size and capability for implantation in different body regions are typically dictated by the battery size. Also, implantable pacemakers have very limited or no capacity for directly responding to the body's endogenous signaling the way the SA node responds to such signaling, i.e. by a modulation of the heart rate relative to the physiological and emotional state (e.g. sleep, rest, stress, exercise).
Recently, biological methods of influencing a patient's cardiac cells have been developed, some of which include administering biopharmaceutical compositions that affect cardiac pacing. Developments in genetic engineering have produced methods for genetically modifying cardiac cells to modify non-pacemaking cardiac cells to acquire pacemaking capabilities or supply stem cells to regenerate the pacing capabilities of cells in the conduction system of the heart. For example, U.S. Pat. No. 6,214,620 describes a method for modulating the excitability of ventricular cells by controlling the regulation of the expression of certain ion channels (for example, K+ channels), and PCT Publication No. WO 02/087419 and WO 05/062890A3 describe methods and systems for modulating electronic behavior of cardiac cells by genetic modification of inwardly rectifying K+ channels (IK1) in quiescent ventricular cells.
Other biological approaches for moderating cardiac pacing involve implanting into the SA node, or other suitable heart regions, cells having particular ion channels that are commonly referred to as hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. Physiologically originating in the SA node, the HCN channels play a prominent role in the control of rhythmic electrical heart, activity. Cyclic nucleotides modulate HCN channel activity, and channel activation occurs upon hyperpolarization rather than depolarization. There are four isoforms of HCN channels (HCN1-4), and each has greater or lesser prevalence in different heart regions. Because the HCN isoforms are directly involved in pacemaker current modulation and activation, implantation of HCN-expressing cells into cardiac tissue that is diseased or experiencing conduction blockage is a viable method for regulating cardiac pacemaker function. See, for example, PCT Publication Nos. WO 02/098286 and WO 05/062958A2 and U.S. Published Application 20090099611.
Biological pacemakers, implemented using gene or cell based therapies, present great potential and promise as therapeutic alternatives to implantable electronic pacemakers for the treatment of cardiac disorders. However, there is a need for effective methods, systems, and apparatus for monitoring the functional maturation over time of the gene therapy or cell therapy approaches involved in establishing a biological pacemaker and for assessing the success or failure of such biological interventions.